Bladder Dysfunction
Bladder dysfunction is caused by abnormal functioning of the bladder tissue resulting in dysuria, irritative symptoms of urgency, frequency and nocturinia and the obstructive symptoms of reduced flow rate, incomplete emptying, hesitancy and increased time to urinate. One type of bladder dysfunction is an overactive bladder. This may be due to a number of factors.
One such cause of an overactive bladder is benign prostrate hyperplasia (BPH), a common condition in aging men. Approximately 80% of men over 50 years of age have varying degrees of urinary bladder outlet obstruction secondary to BPH (Levin et al., 1999, Urology 53:446-450). The bladder dysfunction symptoms are related to the effect of the enlarged prostrate on the urethra which creates a partial urethral obstruction.
The urethral obstruction caused by the enlarged prostrate initiates compensatory changes in the bladder including increased bladder wall thickness, decreased compliance, and detrusor denervation which are mediated by three cellular processes: 1) reduced nerve density; 2) mitochondrial dysfunction and 3) dysregulation of calcium storage and release from the sarcoplasmic reticulum involving Ca2+ATPase dysfunction (see, for example, US 2003/0187059).
Ca2+ATPase activities are approximately 40% lower in bladder samples of men with benign prostate hyperplasia (BPH) mediated bladder dysfunction as compared to Ca2+ATPase levels of bladder samples obtained from men of similar ages with no obstructive symptoms (Levin et al., 1999, Urology 53:446-450). The contractile dysfunctions associated with partial outlet obstruction correlate with disrupted sarcoplasmic reticulum (SR) Ca2+ storage release mechanisms and the degree of the contractile dysfunction is directly proportional to the degradation of sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA) as shown using both enzymatic activity assays and Western blot analysis (see, for example, Zhao et al., 1997, Urology 49: 293-300).
Bladder dysfunction, particularly overactive bladder and more particularly, incontinence and poor detrusor contraction in women all increase as a function of age (reviewed in Li et al., 2009, Urology 74:691-697). A study presented by the Bladder Health Council of the American Foundation for Urologic Disease stated that incontinence affects more than 10 million Americans 85% who are women and affects over 20% of women over the age of 45 and the number increases with age.
In women, alterations in the female sex hormones are believed to play a major role in mediating symptoms of an overactive bladder such as including incontinence, urgency, and frequency due to observed weakness of urethral and pelvic floor muscles and underactive detrusuor smooth muscle contraction in low estrogen states. A possible explanation for the dysfunction is that there is a direct relationship between estrogen levels and blood flow to the bladder and urethral tissue which increases free radical generation and oxidative damage. The oxidative damage associated with estrogen levels as a result of reduced blood flow to the bladder and urethra could account for the decreased Ca2+ATPase activity associated with the bladder and the urethra in low estrogen states such as menopause. Total Ca2+ATPase activity of both the muscle and mucosa was significantly reduced in ovarectomized rabbits (OX) after 28 days indicating that calcium storage and release are compromised after OX (Li et al., 2009, Urology 74:691-697).
Other causes of outlet obstruction that results in bladder dysfunction include but are not limited to cancer, sclerosis or fibrosis of the bladder neck, urethral structure disease, urethral valves, and smooth and striated sphincter dyssynergia, (reviewed in US 2006/0234939). Furthermore, children may suffer from congenital urethral obstruction (U.S. Pat. No. 6,191,156).
An overactive bladder may also occur as a result of neurological damage due to disorders including but not limited to stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy or spinal cord lesions.
Various therapies have been tried to treat bladder dyfunction, particularly overactive bladders. These include but are not limited to anticholinergic agents, prostaglandin inhibitors, beta-adrenergic agonists, COX2 inhibitors, calcium channel modulators (see, for example, U.S. Pat. Nos. 6,444,685, 6,19,156, 6,514,991, 7,459,430). Additionally, it has been observed that phospholamban, an inhibitor of SERCA is present in bladder sarcoplasmic reticulum and may play a role in bladder contractility (Nobe et al., 2001, J. Physiol. 535: 867-878).
Jasmonates
Jasmonates are a family of plant stress hormones that are found in minute quantities in edible plants and characterized by cyclopentone rings. Various uses for jasmonates have been disclosed. Examples include enhancing plant growth (U.S. Pat. No. 5,436,226), repelling insects (U.S. Pat. No. 5,118,711), treating cancer (U.S. Pat. No. 6,469,061) and treating skeletal muscle degeneration caused by malnutrition and disease (U.S. Pat. No. 6,465,021, US Patent Appln. Pub. No. 201000003346), pain relief (WO 2009019693), relieving psychological stress (US Patent Appln. Pub. No. 200700420567), use as a component of a sleep supplement (JP2000355545), treating dry skin (US Patent Appln. Pub. No. 20110085999), treating malodors on fabrics (US Patent Appln. Pub. No. 20110070181) treating heart failure and related disorders (US2011. Jasmonate has also been found to increase Ca2+Atpase in cardiac sarcoplasmic reticulum (see, for example, Antipenko et al., 1997, J. Biol. Chem. 272:2852-60) and skeletal muscle (see, for example, Ioumaa et al., 2002, J. Pharmacol. Exp. Ther. 300:638-46; Starling et al, 1995, Biochem. J. 308:343-6 and Starling et al., 1994, Biochemistry 15:3023-31).